Cancer is the second leading cause of death in the United States, accounting for more deaths than the next five leading causes (chronic respiratory disease, stroke, accidents, Alzheimer's disease and diabetes). While great strides have been made especially with targeted therapies, the prognosis of late stage cancer including melanoma and prostate cancer remains poor. Immunotherapy has recently reemerged as a viable and exciting therapeutic option for advanced stage malignancies. Specifically, it is now recognized that one hallmark of cancer is immune evasion and significant efforts have identified targets and developed therapies to these targets to reactivate the immune system to recognize and treat cancer. In fact, the anti-CTLA-4 mAb, ipilimumab, has for the first time, led to long-term survival of patients suffering from stage III/IV malignant melanoma. Ipilimumab is an immune checkpoint antagonist and interrupts the inhibition of T cells by blocking CTLA-4 (Korman, A., et al., 2005. Tumor immunotherapy: preclinical and clinical activity of anti-CTLA-4 antibodies. Current Opinion in Investigational Drugs 6:582-591). Unfortunately, ipilimumab also leads to generalized (not tumor-specific) activation of T-cell dependent immune responses leading to immune-related adverse effects which can be life-threatening and are often dose-limiting (Weber, J. S., et al., 2008. Phase I/II study of ipilimumab for patients with metastatic melanoma. Journal of Clinical Oncology 26:5950-5956). These include enterocolitis, dermatitis, hypophysitis, uveitis, hepatitis, nephritis and death. Enterocolitis is the most common major toxicity (affecting approximately 20% of patients). The severe safety risks related to immune-mediated adverse reactions prompted the FDA to approve ipilimumab with a Risk Evaluation and Mitigation Strategy (REMS). Recently, coadministration of ipilimumab and a second immune checkpoint modulator targeting PD1 (e.g., nivolumab) has been shown to significantly increase efficacy of immunotherapy of melanoma when compared to ipilimumab alone. This gain, however, was associated with increased frequencies of grade 3/4 adverse effects, which affected more than 50% of patients receiving combination treatment (Wolchok, J. D., et al. 2013. Nivolumab plus Ipilimumab in Advanced Melanoma. N Engl J Med). These findings illustrate the urgent need in the art for strategies to alleviate side effects associated with systemic immune activation while preserving activity of immune checkpoint modulators against malignant disease. Provided herein are compositions and methods addressing these and other problems in the art.